THE WELCH COMPANY
440 Davis Court #1602
San Francisco, CA 94111-2496
415 781 5700
rodwelch@pacbell.net


S U M M A R Y


DIARY: December 1, 2004 07:31 AM Wednesday; Rod Welch

Millie notified Kaiser about worsening condition of IBC symptoms.

1...Summary/Objective
2...Trial Proposal Novel Epothilones BMS-247550 Plus Capecitabine
...........Novel Epothilones BMS-247550 Plus Capecitabine


..............
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CONTACTS 

SUBJECTS
Treatment Trial Zilog Epothilone BMS 247550 Plus Capecitabine Protoc
Red Breast Left Side Rash Worsen Covers More Area Darker Coloration

0504 -
0504 -    ..
0505 - Summary/Objective
0506 -
050601 - Follow up ref SDS 2 025H.
050602 -
050603 - Before Millie left for work this morning, she was worried because the
050604 - rash on her left breast infected with IBC has spread and become
050605 - darker.
050607 -  ..
050608 - Millie submitted a letter to Rosalie saying...
050609 -
050610 -    1.  Thanks for your call yesterday afternoon on a new protocol that
050611 -        I may qualify to try.  I will call you from work to follow up
050612 -        later today.
050614 -  ..
050615 - This
050617 -         ..
050618 -    2.  Could you please let Doctor Johnson know that I started taking
050619 -        the new penicillin medication yesterday, which was prescribed
050620 -        to treat the sore on my breast that has gotten worse from the
050621 -        biopsy taken in April.  This morning the red rash on my breast
050622 -        has spread and darkened considerably compared to the
050623 -        examination yesterday. ref SDS 2 025H  I hope this is a normal
050624 -        reaction to the penicillin treatment, ref SDS 2 6T5G, and not
050625 -        the underlying IBC problem suddenly getting worse?
050627 -         ..
050628 -    3.  I'm at work today, *****************
050630 -         ..
050631 -    4.  Should I continue with the penicillin treatment, or come in for another
050632 -        a visit before our meeting scheduled on 041210 at 1230?
050633 -
050634 -           [On 041202 Millie taken to Emergency Room at Kaiser due to
050635 -           rise in temperature and spread of rash on left breast.
050636 -           ref SDS 4 0001
050637 -
050638 -
050639 -
050640 -
050642 -  ..
0507 -
0508 -
0509 - 1248
0510 -
051001 - Received ref DRT 1 0001 from Rosalie responding to Millie's letter
051002 - earlier today, per above. ref SDS 0 RO5I
051003 -
051004 -    1.  Hi Millie
051005 -
051006 -        I am actually calling you at the number below, however it is
051007 -        the wrong #-Willie Brent?  And I deleted your voice message
051008 -        without writing the number as it was on this email-Sorry!
051010 -         ..
051011 -    2.  I am in my office now
051012 -
051013 -
051014 -
051015 -
051016 -
0511 -

SUBJECTS
Treatment Plan After Avastin Trial Cancelled Due to Blood Clots Phas
Proposal Treatment Plan After Avastin Trial Cancelled Due to Blood C

0804 -
0805 - 1530
080601 -  ..
080602 - Trial Proposal Novel Epothilones BMS-247550 Plus Capecitabine
080603 -
080604 - Millie advised that she called Rosalie, and they discussed the new
080605 - protocol, following up Mil's letter to Rosalie, shown above.
080606 - ref SDS 0 RO5I
080608 -  ..
080609 - Rosalie submitted via fax an explanation and consent forms to
080610 - participate in the new chemotherapy trial, which follows up planning
080611 - with the doctor yesterday, during the meeting at Kaiser. ref SDS 2
080612 - CR5N
080614 -         ..
080615 -        The new trial drug protocol is explaned in one source as
080616 -        replacing Taxol, reviewed below. ref SDS 0 RO3L
080618 -  ..
080619 - Rosalie, also, advised that she forwarded Millie's letter this
080620 - morning, per above, to the doctor so that he is notified about the
080621 - change that has occurred in Millie's breast. ref SDS 0 RO7Q  Rosalie
080622 - also spoke to the doctor about this turn of events.
080624 -  ..
080625 - Millie did not hear from the doctor, and so she continued with the
080626 - combination of coumadin for blood thinner, and penicillin to treat the
080627 - sore on her breast, which was prescribed yesterday.
080628 -
080629 -        [On 041202 Millie taken to Emergency Room at Kaiser due to rise
080630 -        in temperature and spread of rash on left breast. ref SDS 4
080631 -        0001
080633 -  ..
080634 - The protocol received today from the protocol nurse at Kaiser is
080635 - for....
080636 -
080637 -           Novel Epothilones BMS-247550 Plus Capecitabine
080638 -
080639 - ...which will replace Avastin (Bevacizumab) and Taxol.
080641 -  ..
080642 - Capecitabine is one of the treatments Doctor Benz proposed for
080643 - consideration in his 2nd opinion reviewed on 041117. ref SDS 1 OU5V
080645 -  ..
080646 - Millie submitted ref DIT 2, 0001 to Sheridan thanking UCSF and Doctor
080647 - Benz for recommending Capecitabine, and asking for any comments on
080648 - this new trial. ref DIT 2 WG6G
080650 -  ..
080651 - Research shows....
080652 -
080653 -             http://www.clinicaltrials.gov/ct/show/NCT00080262
080654 -
080655 -        Novel Epothilone (BMS-247550) in Patients with Metastatic
080656 -        Breast Cancer (MBC)
080658 -         ..
080659 -        This study is currently recruiting patients.
080661 -         ..
080662 -        Phase II Study started March 2004
080664 -  ..
080665 - Millie's is a Phase III study.
080667 -  ..
080668 - What were results of Phase II study?
080669 -
080670 -        Inclusion Criteria:
080671 -
080672 -        •  Patients must have received all 3 drugs- an anthracycline,
080673 -           taxane, and capecitabine (alone or in combination) and be
080674 -           resistant
080676 -            ..
080677 -        •  No more than 3 prior chemotherapy regimens in the metastatic
080678 -           setting
080680 -            ..
080681 -        •  Must have at least one target lesion that is radiograpically
080682 -           measurable
080684 -            ..
080685 -        •  Good performance status
080687 -            ..
080688 -        •  No history of or current brain or leptomeningeal disease
080689 -
080691 -  ..
080692 - Another source shows Epothilone may replace Taxol...
080693 -
080694 -        March/April 1998
080695 -
080696 -        ScienceWatch
080697 -
080698 -        Will Epothilone Write An Epitaph for Cancer
080700 -         ..
080701 -        The current Hot Ten contains three papers on the same subject:
080702 -        #6, 7, and 10 report the synthesis of epothilone, the
080703 -        forerunner of a new class of anticancer drugs, and ones that
080704 -        can deal with drug-resistant cell lines for breast and colon
080705 -        cancers. Could this compound, or one of its derivatives,
080706 -        possibly repeat the success of the taxol anticancer treatments
080707 -        now in use? Gerhard Hfle of the National Biotechnology
080708 -        Research Institute in Braunschweig, Germany, first extracted
080709 -        epothilones A and B from the myxobacteria Sorangium cellulosum
080710 -        in the late 1980s, and in vitro tests showed A was up to 50
080711 -        times more potent than taxol-and it acted faster. Two years
080712 -        ago he published its chemical structure in Angewandte Chemie
080713 -        (35[13-14]:1567-9, 1996), and this spurred organic chemists to
080714 -        design ways of making it in the laboratory. In just over a
080715 -        year, three groups had achieved this remkable goal, hence
080716 -        papers #6, 7, and 10.
080717 -
080719 -  ..
080720 - Another source shows....
080721 -
080722 -             http://thomsoncurrentdrugs.com/press/2003/asco39/
080723 -
080724 -        BMS 247550
080725 -
080726 -        Targeting the cell cycle: microtubule stabilizers Like the
080727 -        taxanes, epothilones display cytotoxic activity linked to the
080728 -        stabilization of microtubules, resulting in mitotic arrest at
080729 -        the G2/M transition. In an effort to circumvent paclitaxel
080730 -        resistance, a number of epothilones are in clinical
080731 -        development. Candidates in Bristol-Myers Squibb's portfolio are
080732 -        ixabepilone (BMS-247550; Bristol-Myers Squibb Co/GBF GmbH), an
080733 -        epothilone B analog, and BMS-310705 (Bristol-Myers Squibb
080734 -        Co/GBF GmbH), an epothilone A analog; Novartis Pharma AG is
080735 -        developing EPO-906 and Roche's pipeline includes epothilone D
080736 -        (desoxyepothilone B, KOS-862; Kosan Biosciences Inc/Roche
080737 -        Holding AG). Several phase II studies with BMS-247550 will be
080738 -        presented: (i) in patients with NSCLC in whom first-line
080739 -        platinum-based chemotherapy failed; (ii) in patients with
080740 -        hepatobiliary cancer; and, (iii) in patients with metastatic
080741 -        breast cancer previously treated with an anthracycline.
080742 -        BMS-310705 will feature in a phase I study in patients with
080743 -        advanced solid cancer and KOS-862 will feature in a comparison
080744 -        of two schedules in patients with advanced malignancies.
080745 -        Updates on EPO-906 will be presented, specifically phase II
080746 -        colorectal and renal cancer studies and a phase Ib combination
080747 -        study with carboplatin in patients with advanced malignancies.
080748 -
080750 -  ..
080751 - Another sources....
080752 -
080753 -             http://www.asco.org/ac/1,1003,_12-002489-00_18-0023-00_19-00101216,00.asp
080755 -     ..
080756 -    Multi-institutional trial of epothilone B analogue (BMS-247550)
080757 -    with or without estramustine phosphate (EMP) in patients with
080758 -    progressive castrate-metastatic prostate cancer (PCMPC).
080759 -
080761 -     ..
080762 -    Abstract    No: 1584
080764 -     ..
080765 -    Citation:   Proc Am Soc Clin Oncol 22: page
080766 -                394, 2003 (abstr 1584)
080768 -     ..
080769 -    Author(s):  W. K. Kelly, M. D. Galsky, E. Small, B. Rini, W.
080770 -                Oh, P. Kantoff, I. Chen, U. Davar, A. Delacruz, H.
080771 -                Scher; Memorial Sloan-Kettering Cancer Center, New
080772 -                York, NY; University of San Francisco, San Francisco,
080773 -                CA; Dana-Farber Cancer Institute, Boston, MA;
080774 -                MD Anderson Cancer Center, Houston, TX
080775 -
080777 -     ..
080778 -    Abstract:
080779 -
080780 -        BMS-247550 is a semisynthetic analog of the natural product
080781 -        epothilone B which has exhibited preclinical activity in
080782 -        paclitaxel resistant/insensitive cell lines.  Preliminary
080783 -        results of a phase I trial in patients with PCMPC established
080784 -        that BMS-247550 + EMP could be safely administered and is
080785 -        clinically active with 11 of 12 evaluable patients (92%, 95% CI
080786 -        76-100%) showing a 350% post-therapy PSA decline (Smaletz et
080787 -        al, ASCO 2002, abst#732). Subsequently, a multicenter
080788 -        randomized phase II study was performed to determine the
080789 -        efficacy and toxicities of BMS-247550 with or without EMP.
080790 -        METHODS: Chemotherapy nave patients with PCMPC and normal
080791 -        hepatic/renal function are eligible for enrollment.  Patients
080792 -        are randomized to arm A: BMS-247550 (35 mg/m2 IV over 3 hours
080793 -        every 3 weeks) or arm B: BMS-247550 (35 mg/m2 IV over 3 hours
080794 -        every 3 weeks on day 2) + EMP (280 mg po TID days 1-5) +
080795 -        Coumadin 2 mg daily. Forty-six pts per arm is the accrual goal
080796 -        however a 2-stage design with an early stopping rule has been
080797 -        applied such that further accrual in either arm will cease if
080798 -        7 patients out of the first 22 enrolled do not achieve a 350%
080799 -        post-therapy PSA decline. RESULTS: Forty-three patients (arm A:
080800 -        21, arm B:22) have been enrolled with similar median age,
080801 -        performance status, and baseline characteristics between the
080802 -        two arms. The major adverse events are detailed in the table
080803 -        below:(table) Both arms have fulfilled the requirements of the
080804 -        early stopping rule and accrual to both arms continues.
080805 -        CONCLUSION: BMS-247550 with and without EMP is well tolerated
080806 -        with acceptable toxicity. Significant clinical activity had
080807 -        been observed with BMS-247550 alone and in combination with
080808 -        EMP. Phase III randomized trials will be needed to see if the
080809 -        addition of EMP to BMS-247550 improves survival. Support:
080810 -        CTEP, CapCURE, NIH N01-CM17105
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0809 -